Abstract LB385: Immunomodulatory role of MUC5AC in lung adenocarcinoma: A potential therapeutic target

Abstract Lung cancer is the leading cause of cancer-related death worldwide. The most common type of lung cancer is KRAS mutant lung adenocarcinoma (KM-LUAD), which is associated with smoking and lung inflammatory conditions. Despite various approaches and recent discoveries, effective treatments for this aggressive disease remain elusive. Our previous studies along with others demonstrated that the expression of Muc5ac, a main secretory airway mucin, is high in KM-LUAD patients and correlates with poor prognosis. Using a mouse model of KM-LUAD (CC-LR mice), we previously showed that targeting Muc5ac leads to decreased lung tumor burden. Here, we further investigated the immunomodulatory aspects of Muc5ac inhibition and how it impacts tumor progression. To achieve our goal, we used CC-LR mice with and without Muc5ac gene knockout (KO) and compared their tumor microenvironment (TME) at the age of 14 weeks using flow cytometry analysis of the whole lung. We found that the total T cell percentage was significantly elevated in the lung of CC-LR/Muc5ac KO compared to CC-LR mice This increase was accompanied by a marked rise in CD8+ T cell percentage in CC-LR/Muc5ac KO compared to the control group. Additionally, the percentage of IFN-γ+ CD8+ T cells was significantly increased in CC-LR/Muc5ac KO compared to the controls, indicating an enhanced cytotoxic anti-tumor response. Interestingly the percentage of CD4+ T cells was drastically decreased in CC-LR/Muc5ac KO compared to the control group. However, the majority of remaining CD4+ T cells expressed IFN-γ, while the percentage of FOXP3+ CD4+ T cells was decreased, indicating a shift from immunosuppressive T regulatory response to an anti-tumor T helper 1 CD4 T cell response. Although the total NK cell percentage was decreased, the remaining NK cells exhibited higher IFN-γ further suggesting the induction of a cytotoxic TME. In addition, the total percentage of dendritic cells (DCs) was increased with a notable rise in monocytic DCs in the CC-LR/Muc5ac KO group. These findings suggest that the MUC5AC inhibition exerts an anti-tumor and immunostimulatory effect via enhancing the DC response which reprograms the TME from a pro-tumor immunosuppressive phenotype to an anti-tumor cytotoxic phenotype. This further emphasizes the role of mucin in KM-LUAD pathogenesis and that the targeted elimination of MUC5AC could serve as a potential therapeutic target for KM-LUAD patients. Funding: This study was supported in part by a University Cancer Foundation via the IRG program and the retention fund both awarded to SJM. Citation Format: Nastaran Karimi, Michael J. Clowers, Shanshan Deng, Katherine E. Larsen, Selin Oncul, Hani Lee, Avantika Krishna, Yasmina H. Rezai, Farbod Khalaj, Maria T. Grimaldo, Seyed Javad Moghaddam. Immunomodulatory role of MUC5AC in lung adenocarcinoma: A potential therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB385.